Metabolic Syndrome and Cardiometabolic Risk Factors

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Metabolic Syndrome and Cardiometabolic Risk Factors Emilia Papakonstantinoua, Vaia Lambadiaria, George Dimitriadisa and Antonis Zampelasb* a

Second Department of Internal Medicine, Research Institute and Diabetes Center, Athens University, “Attikon” University Hospital, Haidari, Greece; bUnit of Human Nutrition, Department of Food Science and Technology, Agricultural University of Athens, Athens, Greece Abstract: The metabolic syndrome (MetS) is a cluster of metabolic conditions associated to abdominal obesity, such as elevated blood pressure, impaired glucose tolerance, insulin resistance, elevated triglycerides, and low high-density lipoprotein cholesterol concentrations. Each of the associated conditions has an independent effect, but clustering together they become synergistic, making the risk of developing cardiovascular disease (CVD) greater. There is a big debate as to whether the MetS alone or its associated health conditions are more important for CVD incidence and mortality or whether prevention and/or treatment of the MetS will reduce CVD incidence and mortality. This article reviews the evidence that demonstrates that individuals with the MetS are at increased risk for CVD incidence and mortality and discusses these debated issues.

Keywords: Metabolic syndrome, cardiovascular disease, coronary heart disease, diabetes, lipids, blood pressure INTRODUCTION The insulin resistance syndrome initially described by Reaven in 1988 [1], was redefined as metabolic syndrome (MetS) by the National Cholesterol Education Program’s Adult Treatment Panel III report [2, 3], and it is now widely accepted that it is a health situation which increases cardiovascular disease (CVD) risk [4, 5]. The MetS is a collection of associated conditions such as obesity, elevated blood pressure (BP), impaired glucose tolerance (IGT), insulin resistance, elevated triglycerides (TG), and low high-density lipoprotein (HDL) cholesterol concentrations [6]. Each of the associated conditions has an independent effect, but clustering together they become synergistic, making the risk of developing CVD greater. For example, the large international INTERHEART study showed linear relationships between these risk factors and myocardial infarction (MI) [7]. Definitions of the MetS are confusing. Since 1999 several investigators and Organizations have suggested different definitions. Nevertheless, all agree that the characteristics of the MetS include atherogenic dyslipidemia, a prothrombotic state, insulin resistance, hypertension, abdominal obesity, as well as elevated microalbuminuria, increased fibrinogen, decreased plasminogen activator-1 (PA-1), elevated plasminogen activator inhibitor-1 (PAI-1), increased blood viscosity, and increased uric acid [4]. Each abnormality promotes atherosclerosis independently, but when clustered together, these metabolic disorders are increasingly atherogenic and enhance the risk of cardiovascular morbidity and mortality. Moreover, the MetS has been associated with the development of coronary heart disease (CHD), stroke, type 2 *Address correspondence to this author Professor in Human Nutrition, Unit of Human Nutrition, Department of Food Science and Technology, Agricultural University of Athens, Iera Odos 75, Athens 11855, Greece; Tel: +30210-5294701; Fax: +30210-5294701; E-mail: [email protected] 1570-1611/13 $58.00+.00

diabetes mellitus (DM2), diabetic nephropathy, retinopathy, and distal neuropathy. The Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention highlighted that there should be no obligatory component for MetS, but rather all individual components should be considered important on CVD risk prediction [8]. The criteria for diagnosing the MetS according to the report of the adult treatment panel III (ATP III) of the National Cholesterol Education Program are the following: 1) abdominal obesity, given as waist circumference, men > 102 cm and women > 88 cm, 2) fasting glucose 110 mg/dl, 3) BP 130/80 mmHg, 4) TG 150 mg/dl, and 5) HDL cholesterol (men 2 fold increased age-adjusted risk for developing DM2 in nondiabetic subjects [109]. A total of 25%–50% of individuals with prediabetes have the insulin resistance syndrome as defined by NCEP ATP III, and >50% of these individuals have >2 components of the insulin resistance syndrome, placing them at high risk for atherosclerotic CVD. Subjects with isolated IGT have moderate-to-severe insulin resistance in muscle and impaired first- and second-phase insulin secretion, while individuals with impaired fasting glucose have moderate insulin resistance in the liver, impaired first-phase insulin secretion, and normal/near-normal muscle insulin sensitivity [110]. It has been suggested that insulin resistance can predict the extent of coronary artery calcification and CVD independently of classic risk factors in both nondiabetic and diabetic subjects [103, 109, 111-114]. Moreover, in diabetic subjects increase for one standard deviation in the (log) homeostasis assessment model (HOMA) increased the risk of developing a CVD event by about 50% [115]. HOMAestimated insulin resistance was also associated with subsequent symptomatic CVD in the general population independently of all classical (HbA1c, LDL, hypertension) as well as BMI, HDL, TG and several nontraditional risk factors (fibrinogen, oxidized LDL, CRP, VCAM-1, adiponectin) as shown in the Bruneck study after 15 years of follow-up [114]. On the other hand, it was recently shown that insulin resistance is significantly associated with the MetS, but not with angiographically determined coronary artery disease, with the authors suggesting that it may play a greater role in the eventual precipitation of thrombosis than in the gradual progression of atherosclerosis [116]. It has been suggested that insulin resistance progresses toward hyperinsulinemia and hyperglycemia, thus triggering peripheral vasoconstriction and sodium retention [35]. Insulin normally exerts a vasodilating effect after the delivery of a meal, thus increasing peripheral blood flow. However, in insulin-resistant states, even before overt dysglycaemia develops, this effect is blunted, suggesting impairment in insulin action independently of the metabolic disturbance. The latter has been observed in normoglycaemic insulin resistant relatives of subjects with diabetes, in obese nondiabetic individuals, or in subjects with thyroid dysfunction [117-119]. Hepatic production of very-low-density lipoprotein (VLDL) also increases, leading to hypertriglyceridemia, low HDL cholesterol, and consequently atherosclerosis [35]. Hyperin-

Metabolic Syndrome and Cardiovascular Disease

sulinemia enhances de novo lipogenesis and consequently hepatic very-low-density lipoprotein (VLDL) synthesis, via stimulation of sterol regulatory element–binding protein-1c and inhibition of acetyl-coenzyme A–1 carboxylase. It also increases LDL-C transport in smooth muscle cells, promotes collagen synthesis and arterial smooth muscle cell proliferation, and activates multiple genes involved in inflammation [110]. As a result of these lipid imbalances, individuals with the MetS typically exhibit a prothrombotic and proinflammatory state [35]. A major contributor to the development of insulin resistance is circulating NEFAs derived predominantly from TG stores in adipose tissue, which worsen insulin resistance in muscle [120], alter hepatic metabolism [121], and contribute to accumulation of lipid in sites other than adipose tissue [104, 108]. Ectopic lipid accumulation in muscle and liver seemingly predisposes to insulin resistance [120] and dyslipidemia [122]. It has been shown that the elevated postprandial NEFAs in abdominally obese women originate from the non-splanchnic upper body fat, and not from the visceral depot [123], suggesting that visceral fat may be a marker for, but not the source of, excess postprandial fatty acids in obesity. With increasing adipose tissue mass, infiltration of monocyte-derived macrophages occurs and inflammatory cytokines are released leading to paracrine reglulation of lipolysis in adipose tissue and NEFAs release. This local effect promotes additional impairment in the anti-lipolytic effect of insulin, creating more lipolysis [124]. In addition, the adipose tissue of obesity exhibits abnormalities in the production of several adipokines that may separately affect insulin resistance and/or modify risk for CVD. These include increased production of inflammatory cytokines [125], plasminogen activator inhibitor-1 [126], and decreased production of adiponectin [127]. As prediabetes, like overt diabetes, is currently considered a CVD equivalent, aggressive multifactor treatment and lifestyle intervention should probably be initiated early in this stage. The ACT-NOW study showed that treatment with pioglitazone reduced the risk of conversion of IGT to DM2 by 72%, although with the cost of weight gain and edemas. In high risk individuals, pharmacologic intervention with low doses of pioglitazone and metformin, should be initiated to prevent the progression of IGT/IFG to overt DM2 [110]. However, up to now, no pharmacologic treatment has received official licence for this stage of the disease. Glucose excursions damage the endothelium through the following mechanisms: a). Advanced glycation of proteins/end products (AGEs) AGEs are a complex group of compounds formed via a nonenzymatic reaction between reducing sugars and amine residues on proteins, lipids, or nucleic acids. In diabetes, AGE accumulation may result from chronic hyperglycaemia and also with concomitant impaired renal function because the kidney is the major site of AGE clearance [128]. Glycation involves the formation of chemically reversible early glycosylation products with proteins, so called Schiff bases and Amadori products, (e.g. HbA1c). These early products undergo slow and complex rearrangements to form advanced glycation end-products (AGEs) [129]. AGEs enhance endo-

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thelial dysfunction, reduce LDL uptake, thus elevating plasma levels of oxidized LDL, promote destabilization of the atherosclerotic plaque, and inhibit vascular repair after injury [128]. A positive correlation of tissue AGE concentration and the severity of the atherosclerotic plaque have been demonstrated [130]. In states of increased oxidative stress, such as diabetes and inflammation, there is increased accumulation of AGEs within various tissues. The intermolecular collagen crosslinking caused by AGEs, leads to diminished arterial and myocardial compliance and increased vascular stiffness, phenomena that are considered to explain partly the increase in diastolic dysfunction and systolic hypertension seen in diabetic subjects [128, 131]. b). Activation of the DAG (diacylglycerol) – PKC (protein kinase C) metabolic pathway Protein kinase-C (PKC) is a family of multifunctional isoenzymes, activated by diacylglycerols, which play a major role in signal transduction and intracellular crosstalk. Activation of one or more isoforms of PKC induces various biological procedures, such as changes in cell proliferation and differentiation, transmembrane ion transport, glucose and lipid metabolism, smooth muscle contraction, vascular permeability and gene expression [132]. A major physiological significance of PKC is its effect on insulin’s action. Several PKC isoforms can inhibit the metabolic actions of insulin by inhibiting the PI3K pathway, while enhancing insulin’s growth-promoting actions via the MAPK pathway. Such PKC isoforms have been reported to be changed in diabetes or increasing glucose levels of media in vascular cells. The latter is partly due to increased de novo synthesis of DAG by glucose and further activation of PKC- isoform mainly [133]. Interventions that increase DAG metabolism (i.e. Vitamin E), and or inhibit PKC isoenzymes (i.e. LY333531, ruboxistaurin) improve the consequences of DAG-PKC activation in experimental diabetes. c). Activation of the polyol metabolic pathway Aldose reductase is a multifunctional enzyme that reduces aldehydes. Under diabetic conditions aldose reductase converts glucose into sorbitol, which is then converted to fructose [134]. In tissues that do not require insulin for cellular glucose uptake, such as the kidney, retina, nerves and blood vessels, hyperglycaemia activates the polyol pathway, resulting in the formation of sorbitol. Aldose reductase is a rate-limiting enzyme in the polyol pathway and reduces the aldehyde form of glucose to sorbitol. Several experimental and clinical studies have evidenced a link between the increased polyol pathway activity and the occurrence of chronic diabetic complications, as elevated levels of sorbitol are considered to be toxic [135]. A high polyol pathway consumes large quantities of ATP and NADPH, which is required for the functioning of many endothelial enzymes, including nitric oxide synthase and cytochrome P450, as well as for the antioxidant activity of glutathione reductase [135]. d). Increased oxidative stress Oxidative stress is defined as an increase in the steadystate levels of reactive oxygen species and may occur as a

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result of increased free radical generation and/or decreased anti-oxidant defense mechanisms. Several studies have reported decreased plasma or tissue concentrations of superoxide dismutase, catalase, glutathione and ascorbic acid in both clinical and experimental diabetes. Moreover, diabetes has been associated with an increased generation of oxygenderived free radicals [135]. The latter impair endotheliumdependent vasodilatation through inactivation of nitric oxide [136]. Apart from atherosclerosis, hyperglycemia-induced oxidative stress contributes to the development of microvascular pathogenesis in the diabetic myocardium, which results in myocardial cell death, hypertrophy, fibrosis, abnormalities of calcium homeostasis and endothelial dysfunction [137]. Increased oxidative stress can also activate NF-kB and numerous serum inflammatory markers such as MCP-1, IL-6, TNF, troponin or C-reactive protein (CRP), which have been linked to cardiovascular dysfunction in diabetics [138]. Recently, it was proposed that exposure to NEFAs activated oxidative stress and production of prothrombotic markers and decreased expression of insulin receptors in cultured human hepatocytes, which might contribute to the increased CVD risk [139]. NEFAs also impair the endothelial function [140], which is a predictor of clinical CVD events [141] and are associated with sudden death [142]. e). Activation of the exosamine metabolic pathway The enzymes of O-GlcNAc cycling couple the nutrientdependent synthesis of UDP-GlcNAc to OGlcNAc modification of Ser/Thr residues of key nuclear and cytoplasmic targets. This series of reactions culminating in OGlcNAcylation of targets has been termed the Hexosamine Biosynthetic Pathway (HBP). These enzymes in turn influence pathways of anabolism/catabolism and growth [143]. Under normal conditions, the HBP acts as a fuel sensor and repartitions fuel substrates into suitable storage depots within the body. In diabetes, the hexosamine biosynthetic pathway is over activated. Chronically activated HBP flux is maladaptive, contributing to pathophysiologic phenotypes, e.g., insulin resistance, mitochondrial impairment, increased oxidative stress, apoptosis and cell death [144]. Several RCTs have shown that lifestyle interventions are very successful at decreasing the risk of developing DM2 in people with IGT. Results from the Finnish Diabetes Prevention Study that investigated the effect of early-phase insulin secretion on the incidence of DM2 in 443 individuals with IGT; randomized to lifestyle intervention of control group and followed-up for 4 years, showed that the reduction in the risk of developing DM2 after lifestyle intervention is related to the improvement of insulin sensitivity along with weight loss [145], but after 10 years of follow-up lifestyle intervention among persons with IGT did not decrease CVD morbidity [146]. The Diabetes Prevention Program investigators [147] assessed the effects of lifestyle intervention, metformin and placebo on CVD risk factors and markers of the MetS among subjects with IGT and showed that compared with the placebo and metformin arms, subjects assigned to the lifestyle intervention showed decreased BP, increased HDL cholesterol levels and lower TG levels during approximately 3 years of follow-up. Intensive lifestyle modification was also associated with a reduction in the more atherogenic small, dense LDL particles [147].

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In conclusion, people with MetS, especially if they are abdominally obese, are at an increased risk for developing DM2, but there is no convincing data that MetS predicts the development of prediabetes states or DM2 or that by treating diabetes successfully will reduce CVD incidence or mortality. Moreover, although insulin resistant individuals are at an increased risk for MetS and DM2, it is not clear whether insulin resistance alone increases CVD incidence and mortality. METABOLIC SYNDROME, OBESITY, FAT DISTRIBUTION AND CARDIOVASCULAR RISK It is generally agreed that people with MetS are at an increased risk of obesity. Data from the NHANES 2003– 2006 showed that the age-adjusted prevalence of MetS related to overweight/obesity and insulin resistance, was approximately 34% (35.1% among men and 32.6% among women) [148]. However, it is not clear whether MetS can predict type of adiposity (visceral vs. subcutaneous) or that treating obesity will reduce the risk for MetS or CVD. Obese individuals and those with preexisting diabetes also have a double CVD risk when the MetS is present [21, 24]. It has been suggested that overweight is more consistently associated with CHD or CVD mortality than with allcause mortality, with hazard ratios for higher degrees of overweight (typically body mass index, BMI, in the 27.5 to 29 kg/m2 range) of 1.4 to 2.8 over 10 to 26 years of followup [149-152]; whereas BMI in the lower range of overweight sometimes [150, 153], but not always, [149, 150, 154] was associated with CVD mortality risk. Data on stroke are mixed, with borderline increased risk in overweight in some studies [155], but not all [150, 156]. Moreover, it has been suggested that the relationship of CVD mortality with overweight may be influenced by the presence of CVD risk factors, as shown in a study that reported an excess risk of CVD mortality among overweight men and women with hypertension, but not among those without it [157]. A study with 2970 adults with DM2, aged 30-79, from a French national sample that examined whether obesity alone or as part of the MetS increases CHD risk reported that a 20% increased odds of CHD was estimated for every 5 kg/m2 BMI increase (P=0.0001), suggesting that obesity alone, and particularly when the MetS is present, increases CHD risk in people with DM2 [32]. On the other hand, results from the DECODE Group from data based on 9 European population-based studies with 7782 men and 7739 women (aged 30-89 years), with a median follow-up of 8.55 years, that evaluated whether the MetS, including abdominal adiposity as a mandatory element, predicts CVD mortality better than the cluster of other abnormalities not including abdominal adiposity, showed that the ratio for CVD mortality in men and women with the MetS was 2.44 (95% CI, 1.69-2.98) and 2.32 (95% CI, 1.27-4.23); in non-obese men with 2 and > or = 3 factors the hazard ratio was 1.60 (95% CI, 1.12-2.30) and 2.44 (95% CI, 1.62-3.66), respectively, and in non-obese women with 2 factors the hazard ratio was 2.41 (95% CI, 1.09-5.33), suggesting that the cluster of the CVD risk factors predicted CVD mortality regardless of the presence or absence of the abdominal adiposity [158]. It has been proposed that the predominant underlying risk factors for the MetS and CVD appear to be excess abdominal


fat [105, 159] and insulin resistance [1, 160]; whereas low muscle mass does not seem to be involved in MetS [161]. It has been suggested that a person with inherent insulin resistance can develop the MetS with only moderate excess in abdominal fat [162], but even people with little or no inherent insulin resistance can develop the MetS if they accumulate excess abdominal fat [163]. Abdominally obese individuals are at a 80 – 90% greater risk for developing DM2 as compared to obese individuals with different body fat distribution [85]. Numerous organizations now recommend the measurement of waist circumference in addition to the BMI to estimate the amount of abdominal fat, supporting the central importance of abdominal obesity in the MetS [164]. Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort with 1,868 men and 1,939 women aged 30–64 years at baseline with a 9 years follow-up reported that in people with MetS an increase in their waist circumference increased cardiometabolic risk factors [165]. After accounting for changes in BMI, reducing waist circumference by 3 cm significantly reduced MetS incidence only in women, whereas increasing waist circumference by 7 cm increased the odds ratios for incident MetS in both men (7.9, 95% CI, 4.4–13.9) and women (4.7, 95% CI, 2.7–8.0), compared with a stable waist circumference [165]. Results from 2377 normotensive nondiabetic Chinese adults aged 30 years who were reexamined 10 years after their baseline examination, both baseline waist circumference and waist circumference change were significant predictors of follow-up systolic BP or incident hypertension, independent of the effects of obesity [166]. A standardized case-control study that assessed the relation between BMI, waist and hip circumference, and waist-to-hip ratio (WHR) to MI in 27,098 participants in 52 countries (12,461 cases and 14,637 controls), showed that WHR was significantly associated with MI risk worldwide [167]. On the other hand, the Health, Aging and Body Composition Study that assessed the association between body fat distribution, particularly visceral adipose tissue, and incident MI in 1,116 well-functioning men and 1,387 women aged 70-79 years showed that during an average follow-up time of 4.6 years, there was no association between incident MI and the adiposity or fat distribution variables for men [168]. However, in that study visceral adipose tissue, but not BMI or total fat mass, was found to be an independent predictor of MI (HR = 1.67, 1.28, 2.17, p < 0.001) only in women [168]. Another study showed that for a given waist circumference, higher total thigh adipose tissue and total thigh subcutaneous adipose tissue masses were associated with lower HbA1c and LDL:HDL ratio, whereas hip circumference was inversely associated with fasting insulin, HbA1c, and PA-1, suggesting that the combined use of both circumferences can contribute to identify individuals at high risk for CVD [169]. The physiological metabolic action of adipose tissue is fat storage in the form of triglycerides. In the fasting state, adipose tissue depots normally release non-esterified-fatty acids (NEFA) after lipolysis of the stored triglycerides. Postprandially, the raise in insulin concentration suppresses lipolysis, through inhibition of hormone-sensitive-lipase (HSL), the key enzyme sited within the adipocyte. Hence, the concentration of circulating NEFAs is abruptly sup-


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pressed after meal ingestion. In addition, lipoprotein-lipase (LPL), an insulin-dependent enzyme situated on the surface of the arterial wall, is activated. The latter results in the breakdown of circulating postprandial triglyceride-rich chylomicrons and a subsequent incorporation of NEFAs into triglycerides for further storage. The whole procedure is dependent of adipose tissue blood flow, which normally increases when insulin rises after a meal [170, 171]. Adipose tissue function is impaired in obesity and insulin resistance. Lipolysis is down regulated, the sensitivity of lipolysis to insulin is reduced and there are disturbances in the regulation of adipose tissue blood flow [172]. More specifically, adipose tissue blood flow response is blunted postprandially in insulin resistant states, such as DM2, impaired glucose tolerance, obesity, and even in normoglycaemic 1st degree relatives of diabetic individuals [118]. Not all adipose tissue depots behave in the same way. Increased upper body fat is strongly associated with the insulin-resistance syndrome and CVD risk factors. Paradoxically, increased lower body fat does not confer the same risk of cardiovascular disease and insulin resistance as the same amount of fat in the upper body; in fact, lower body fat appears to exert a protective effect [173]. The proportion of abdominal to gluteofemoral body fat correlates with obesityassociated diseases and mortality. In day-to-day metabolism lipolysis appears to be more passive in gluteofemoral depot than the abdominal one, and it exerts its protective properties by long-term fatty acid storage. Moreover, a beneficial adipokine profile is associated with gluteofemoral fat. Plasma leptin and adiponectin concentrations are positively associated with gluteofemoral fat while the level of inflammatory cytokines is negatively associated. Finally, loss of gluteofemoral fat has been associated with an increased metabolic and cardiovascular risk [174]. Gluteofemoral fat acts through a long-term entrapment of excess fatty acids, thus protecting from the adverse effects associated with ectopic fat deposition [174]. Because of the effects of obesity on insulin resistance, weight loss is an important therapeutic objective for overweight or obese individuals who are at risk for MetS [175]. The multifactorial intensive lifestyle intervention employed in the Diabetes Prevention Program, which included reduced intake of fat and calories, led to weight loss averaging 7% at 6 months and maintenance of 5% weight loss at 3 years, and was associated with a 58% reduction in incidence of DM2 [176]. However, a RCT looking at high-risk individuals in Spain showed the Mediterranean dietary pattern reduced the incidence of diabetes in the absence of weight loss by 52% compared with the low-fat diet control group [177]. Oneyear results of the intensive lifestyle intervention in the large Look AHEAD (Action for Health in Diabetes) RCT showed in individuals with diabetes that an average 8.6% weight loss leads to significant reduction of A1C as well as reduction in several CVD risk factors [178], with benefits sustained at 4 years [179]. In conclusion, the MetS combined with obesity, particular central obesity, increases the risk of several CVD risk factors, but it is unknown whether treating obesity will reduce CVD incidence or mortality.

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METABOLIC SYNDROME, DYSLIPIDAEMIA AND CARDIOVASCULAR RISK People with MetS are at an increased risk for developing dyslipidaemia and dyslipidaemia increases CVD risk, but it is unclear whether successful treatment will reduce CVD incidence and mortality. This argument is well justified because in the last 20 years there are dramatic reductions in CVD risk due to newer and more suitable pharmacologic agents, such as the statins, but CVD mortality continues to rise. Lipid metabolism can be disturbed in different ways, leading to changes in plasma lipoprotein function and/or levels [180]. This by itself and through interaction with other CVD risk factors may affect the development of atherosclerosis [180]. The atherogenic dyslipidemia is characterized by elevated concentrations of TG, low levels of HDL, and small, dense LDL particles and has been found to be predictive of a 20-fold increased risk of coronary artery disease among middle-aged men in the Quebec Cardiovascular Study [181]. There is ample evidence from RCTs showing that reducing TC and LDL cholesterol can prevent CVD [180]. For every 39 mg/dl decrease in LDL, CVD risk is reduced by 21% [182]. Hypertriglyceridemia, but not hypercholesterolemia, is associated with insulin resistance. The frequency of hypercholesterolemia is not increased in subjects with DM2. However, elevated LDL cholesterol acts synergistically with other risk factors to accelerate atherogenesis [183]. Many studies further suggest that the smallest particles in the LDL fraction carry the greatest atherogenicity, because they are more toxic to the endothelium, more able to transit through the endothelial basement membrane, more likely to adhere to arterial wall glycosaminoglycans, have increased susceptibility to oxidation and/or are more selectively bound to scavenger receptors on monocyte-derived macrophages [184, 185]. The atherogenic potential of lipoprotein remnants and small LDL could be confounded in part by their common association with an increased total number of apoB-containing lipoproteins in circulation [7, 186]. Several studies clearly demonstrated that high concentrations of apoprotein B can predict CVD [187, 188]. In some studies high apoprotein B represented a risk factor even stronger than total or LDL. Each LDL particle contains one molecule of apoprotein B. Therefore, the higher the number of circulating apoprotein B molecules, the higher is the number of LDL circulating particles. In the MetS, serum LDL is not significantly increased [189], whereas apoprotein B levels are higher [189]. This means that the number of LDL particles is increased in subjects with the MetS and these particles are smaller and denser. This change in LDL composition is attributable to relative depletion of non-esterified cholesterol, esterified cholesterol and phospholipid with either no change or an increase in LDL-TG [190]. The direct relationship between small dense LDL and the natural history of atherosclerotic CVD is not entirely accepted [191, 192], with some studies showing that this alteration in LDL composition is an independent risk factor for CVD [193], but others showing that most often the association between particle composition and atherosclerotic CVD events is not independent, but related to the concomitant changes in other lipoproteins and other risk factors [194].

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Low HDL cholesterol is a common feature of subjects with central obesity, DM2, and the MetS, and is considered as an independent determinant of increased CVD risk [182]. It has been proposed that for every 1 mg/dl increase in HDL, CVD risk is reduced by 2-3% [182]. It has been proposed that low levels of HDL are a consequence of changes in HDL composition and metabolism. HDL cholesterol appears to confer protection from atherosclerosis, due to its ability to remove cellular cholesterol, as well as it anti-inflammatory, antioxidant and antithrombotic properties, which improve endothelial function and inhibit atherosclerosis [182]; but HDL may be modified to become pro-inflammatory [195]. The ability of HDL to inhibit or paradoxically to enhance vascular inflammation, lipid oxidation, the atherosclerotic plaque growth and thrombosis reflects changes in specific enzyme and protein components, e.g. increases in serum amyloid A, an acute-phase reactant and pro-inflammatory molecule [196]. Results from the ENTRED study with 2970 adults with DM2, aged 30-79 years, from a French national sample reported that higher levels of HDL in subjects with DM2 with MetS and without MetS, were associated with approximately 1.3 –fold lower CHD risk, suggesting that high levels of HDL may modify the risk of CHD imposed by obesity and/or MetS [32]. However, although high plasma levels of HDL cholesterol are considered as a beneficial marker, there is a question whether pharmacologic increases in HDL cholesterol levels improve clinical outcomes. It has been suggested that Cholesterol efflux capacity from macrophages, a metric of HDL function, rather than a static measurement of its level, has a strong inverse association with both carotid intimamedia thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. Cholesterol efflux capacity, an integrated measure of HDL quantity and quality, is reflective of the role of HDL in atheroprotection and can be improved after pioglitazone administration [197]. The AIM-HIGH study, conducted among subjects with atherosclerotic CVD and LDL cholesterol levels 70 mg/dl, showed no incremental clinical benefit from the addition of niacin to statin therapy during a 36 month follow-up period, despite significant improvements in HDL cholesterol and TG levels. [198]. The latter could indicate the need for early intervention aiming beyond static lipid levels. A disorder of TG metabolism is a key feature of the MetS that increases risk of both ischaemic heart disease and DM2 by approximately 3 fold [199]. The role of a raised plasma TG level as a predictor of CVD has been debated for many years [180]. Some have reported that even mild TG elevations can significantly increase the risk of MI and stroke [200, 201]. Fasting TG levels relate to CVD risk, but the effect is attenuated by adjustment for other factors, especially HDL cholesterol, whereas non-fasting TG are strongly associated with CVD risk independently of the effects of HDL [180]. The increased CVD risk related to elevated TGs is more evident in subjects with a concomitant hypercholesterolemia. Elevated TGs cause a decrease in the cholesterol ester content of the lipoprotein core, which leads to a decrease in HDL cholesterol concentration with smaller denser particles [202]. Studies implicate VLDL and their remnants and chylomicron remnants in atherosclerosis development,


due to their capacity to activate platelets and the coagulation pathway, but the concomitant alterations in other lipoproteins and other risk factors obscure any conclusions about direct relationships between disease and TGs [203]. A study showed that serum TG concentrations in obese subjects with similar levels of visceral adiposity were increased by the combination of increased secretion and severely impaired clearance of VLDL particles [204]. Furthermore, increased liver and subcutaneous abdominal fat were linked to increased secretion of VLDL particles, whereas increased plasma levels of apolipoprotein C-III were associated with impaired clearance in obese hypertriglyceridemic subjects [204]. Several studies have demonstrated that non–HDL cholesterol is a better predictor of CVD than the LDL cholesterol concentration. Non–HDL cholesterol represents the difference between total cholesterol and HDL concentrations and reflects the amount of cholesterol within those lipoprotein particles that have been demonstrated to be atherogenic [205, 206]. For the great majority of people with prediabetes or diabetes in whom the LDL goal is 70 mg/dL, the non–HDL goal will be 100 mg/dL. Interventional strategies for treating non–HDL-C include use of low-fat diet, niacin, fibrates, pioglitazone, and omega-3 fatty acids, in combination with statins, which is considered the milestone in treating atherogenic dyslipidemia in this population [110]. In conclusion, the MetS increases the risk of developing dyslipidaemia. Elevated concentrations of small dense LDL particles and low HDL cholesterol increase the risk of developing CVD, whereas the association between elevated TG concentrations and CVD is less certain, but intensive treatment of dyslipidaemia has failed to decrease CVD mortality.


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of DM2 [210]. Hypertension damages the vascular wall by endothelial dysfunction, which is the first step in the atherosclerotic process [211] and can predict subsequent clinical vascular events [141, 212]. Even a small increase in BP can predispose to clinical events [213]. Epidemiologic analyses show that BP >115/75 mmHg is associated with increased CVD event rates and mortality in individuals with diabetes [65, 214, 215]. RCTs have demonstrated the benefit (reduction of CHD events, stroke, and nephropathy) of lowering blood pressure to